Stuart E. Turvey, MB, BS, DPhil,a and David H. Broide, MB, ChBb
Recent years have witnessed an explosion of interest in the innate
immune system. Questions about how the innate immune system
senses infection and empowers a protective immune response are
being answered at the molecular level. These basic science
discoveries are being translated into a more complete
understanding of the central role innate immunity plays in the
pathogenesis of many human infectious and inflammatory
diseases. It is particularly exciting that we are already seeing a
return on these scientific investments with the emergence of novel
therapies to harness the power of the innate immune system. In
this review we explore the defining characteristics of the innate
immune system, and through more detailed examples, we
highlight recent breakthroughs that have advanced our
understanding of the role of innate immunity in human health and
disease. (J Allergy Clin Immunol 2010;125:S24-32.)
Abbreviations used
DAMP: Damage-associated molecular pattern
IPAF: IL-1b-converting enzyme (ICE) protease-activating factor
IRAK4: IL-1 receptorassociated kinase 4
MAL: MyD88 adapter-like
MPL: Monophosphoryl lipid A
MyD88: Myeloid differentiation primary response gene 88
NK: Natural killer
NLR: Nucleotide oligomerization domainlike receptor
NLRP3: NLR family, pyrin domain-containing 3
NOD: Nucleotide oligomerization domain
SNP: Single nucleotide polymorphism
TIR: Toll/IL-1 receptorlike domain
TIRAP: Toll/IL-1 receptorlike domaincontaining adaptor protein
TLR: Toll-like receptor
From athe Department of Paediatrics, BC Childrens Hospital and Child & Family Research Institute, University of British Columbia; and bthe Department of Medicine,
University of California San Diego, La Jolla.
S. E. T. is supported by a Chaim Roifman Scholar Award from the Canadian
Immunodeficiency Society and a Career Development Award from the Canadian
Child Health Clinician Scientist Program (CCHCSP)-a CIHR Strategic Training
Program and operating grants from the Canadian Cystic Fibrosis Foundation and the
CIHR Team in Mutagenesis and Infectious Diseases. D.H.B. is supported by NIH
grants AI 038425, AI072115 and AI070535.
Disclosure of potential conflict of interest: The authors have declared that they have no
conflict of interest.
Received for publication May 14, 2009; revised July 3, 2009; accepted for publication
July 8, 2009.
Reprint requests: Stuart Turvey, MB, BS, DPhil, FRCPC, Division of Infectious and Immunological Diseases, BC Childrens Hospital and Child & Family Research Institute,
University of British Columbia, 950 West 28 Ave, Vancouver BC V5Z 4H4, Canada.
E-mail: sturvey@cw.bc.ca.
0091-6749/$36.00
2010 American Academy of Allergy, Asthma and Immunology
doi:10.1016/j.jaci.2009.07.016
S24
FIG 1. Integrated human immune system. The human microbial defense system can be simplistically
viewed as consisting of 3 levels: (1) anatomic and physiologic barriers; (2) innate immunity; and (3) adaptive
immunity. In common with many classification systems, some elements are difficult to categorize. For
example, NK T cells and dendritic cells could be classified as being on the cusp of innate and adaptive
immunity rather than being firmly in one camp.
TABLE I. Overview of defining features of innate and adaptive immunity: Comparing and contrasting some of the defining features of
the innate and adaptive immune systems
Innate immune system
Cellular elements
Humoral elements
Receptor characteristics
Ligands recognized
Types of receptors
Response time
Immunologic memory
Risk of autoreactivity
Specific examples
Receptor families
Receptor
TLRs
TLR4
TLR5
NOD-like receptors
NOD2
IPAF
MBP
NLRP3 (or NALP3)
Collectin family
NOD-like receptors
RAGE family
MHC class Ispecific inhibitory
receptors
RAGE
KIR
CD94-NKG2A
heterodimers
Ligand
LPS
Flagellin (extracellular)
Muramyl dipeptide
Flagellin (intracellular)
Microbial terminal mannose residues
Uric acid, K1 efflux, ATP
HMGB1, S100
Self MHC class I (inhibitory signal)
Self MHC class I (inhibitory
signal)
RAGE, Receptor of advance glycation end product; HMGB1, high mobility group box 1.
molecules that are upregulated and released during the cell lysis
and tissue damage that occurs in the context of both infectious
and sterile inflammation. Well-characterized DAMPs include
high mobility group box 1 protein and other endogenous alarmins,
heat shock proteins, and uric acid.
In the third innate immune recognition strategy, innate immune
receptors detect missing self, molecules expressed by normal
healthy cells but not expressed by infected cells or microbes.
Recognition of these signals indicates that all is well, and an
inhibitory signal is delivered to prevent activation of the immune
response against host tissues. This inhibitory system is well
illustrated by NK cells. Inhibitory receptors specific for self
MHC class I molecules play a central role in missing-self
recognition by NK cells, ensuring NK cells preferentially attack
infected cells that downregulate their MHC class I proteins.9
repertoire of conserved microbial products; for example, wellcharacterized receptor-ligand pairs include TLR4 and LPS, TLR5
and flagellin, and TLR1/TLR2/TLR6 and lipoproteins. Collectively, the complete TLR family allows the host to detect infection
by most (if not all) types of microbial pathogens. For example,
gram-positive organisms, such as Streptococcus pneumoniae, are
initially recognized by TLR1, TLR2, TLR4, TLR6, and TLR9,
which in turn interact with a range of downstream signaling molecules to activate an inflammatory cascade. TLR signaling pathways have been the focus of considerable attention (Fig 2).12,13
The emerging model has ligation of microbial products by
TLRs culminating in the activation of nuclear factor kB, activator
protein 1, interferon regulatory factor 3, and other transcription
factors, driving the production of proinflammatory cytokines,
maturation of dendritic cells, and other immunologic responses.
Human disease resulting from TLR defects. Naturally
occurring genetic mutations in human subjects causing extreme
immunodeficiency phenotypes present powerful opportunities to
determine the relationship between specific immunologic defects
and human disease processes in vivo. Recent description of human primary immunodeficiencies associated with abnormal
TLR signaling demonstrates that this pathway is critical for human defense against infection. Empowered by technologic advances in genotyping and bioinformatics, we are now beginning
to appreciate how common genetic variation and polymorphisms
in genes controlling the innate immune response alter infectious
susceptibility in a subtle but specific fashion. Importantly, human
primary immunodeficiencies associated with abnormal TLR signaling provide unique insights into the immunologic pathways vital for host defense and identify candidate genes that might cause
subtle immunodeficiencies in the broader population of apparently healthy persons.14
Monogenic primary immunodeficiencies. IL-1 receptorassociated kinase 4 (IRAK4) deficiency (OMIM #607676)15
and myeloid differentiation primary response gene 88 (MyD88) deficiency (OMIM #612260)16 are novel primary immunodeficiencies specifically affecting TLR function. MyD88 and IRAK4
are binding partners involved in downstream signaling from most
TLRs (Fig 2); hence the clinical and laboratory phenotypes of
IRAK4 and MyD88 deficiencies are identical. The narrow spectrum of infections experienced by affected individuals is striking
in light of their profound impairment of TLR function and pathogen
sensing. IRAK4- and MyD88-deficient patients predominantly experience recurrent infections caused by pyogenic gram-positive
FIG 2. Overview of TLR signaling and the NLRP3 inflammasome. TLR ligation initiates a signaling cascade
that culminates in the translocation of the transcription factor nuclear factor kB (NF-kB) and others to the
nucleus, generating an acute inflammatory response. The NLRP3 (or NALP3) inflammasome is triggered
by a wide variety of stimuli, culminating in the activation of caspase 1, which will then cleave proIL1b and proIL-18 to drive an inflammatory response. Human mutations and polymorphisms in many of
the genes encoding elements of these pathways appear to alter susceptibility to infectious and inflammatory diseases. TRAF6, TNF receptor-associated factor 6; TAK1, Transforming growth factor-beta-activated
kinase 1; IKK, I-kappa-B kinase; ASC, Apoptosis-associated speck-like protein containing a card.
bacteria, with Streptococcus pneumoniae causing invasive infection in all reported cases and Staphylococcus aureus and Pseudomonas aeruginosa causing infections in about half the patients.
The surprising clinical observation that IRAK4-deficient patients
are resistant to viral infections was recently explained at a molecular level because IRAK4-deficient patients are able to control viral
infections by means of TLR3- and TLR4-dependent production of
interferons.17
NLRs
Overview of NLR structure and function. Although
TLRs are outward-looking innate immune receptors detecting
microbial signatures either in the extracellular milieu or engulfed
in the lumen of endocytic vesicles, NLRs are a recently appreciated family of receptors that survey the intracellular environment.25,26 In common with other innate immune receptor
systems, the NLRs have ancient origins, being structurally reminiscent of plant R-proteins that mediate plant cell defense against
pathogenic bacteria. NLRs sense microbial products and metabolic stress, driving inflammation through the formation of an inflammasome: a large cytoplasmic complex that activates
inflammatory caspases and the production of the cytokines IL1b and IL-18.27
The human NLR family consists of at least 23 members and can
be structurally divided into 4 subfamiles based on N-terminal
effector domains.28 The first NLRs reported to have a direct function as intracellular pathogen detectors were NOD1 and NOD2.26
Both NOD proteins detect distinct substructures generated during
the synthesis, degradation, and remodeling of bacterial peptidoglycan, ensuring the recognition of peptidoglycan from both
gram-positive and gram-negative bacteria. IL-1b-converting
enzyme (ICE) protease-activating factor (IPAF) is another member of the NLR family known to detect bacterial pathogens.29
IPAF partners with TLR5 to detect infection by flagellated bacteria: TLR5 senses extracellular flagellin, whereas IPAF focuses on
intracellular flagellin. In addition to sensing microbial products,
NLRs can sense metabolic stress related to infection and sterile
inflammation. This sensing capacity is best demonstrated by
NLRP3 (NLR family, pyrin domain-containing 3).30 When triggered, NLRP3 (also called NALP3 or cryopyrin) activates the caspase 1 inflammasome, leading to IL-1b and IL-18 processing (Fig
2). The NLRP3 inflammasome appears to be activated by common metabolic danger signals, such as potassium efflux, which
occurs during inflammation because of disruption of the plasma
membrane or increased extracellular ATP released by injured
cells. Other clinically relevant NLRP3 activators include uric
acid, asbestos, silica, and alum.
Role of NLRs in human health and disease. Although
our molecular appreciation of NLRs is very recent, this class of
innate immune receptors plays a central role in several human
occur directly through the triggering of the NALP3 inflammasome by alum crystals or indirectly through release of the endogenous danger signal uric acid, which subsequently activates
NLRP3.
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